FTO genotype impacts food intake and corticolimbic activation

Abstract

Background: Variants in the first intron of the fat mass and obesity-associated (FTO) gene increase obesity risk. People with "high-risk" FTO genotypes exhibit preference for high-fat foods, reduced satiety responsiveness, and greater food intake consistent with impaired satiety.

Objective: We sought central nervous system mechanisms that might underlie impaired satiety perception in people with a higher risk of obesity based on their FTO genotype.

Design: We performed a cross-sectional study in a sample that was enriched for obesity and included 20 higher-risk participants with the AA (risk) genotype at the rs9939609 locus of FTO and 94 lower-risk participants with either the AT or TT genotype. We compared subjective appetite, appetite-regulating hormones, caloric intake at a buffet meal, and brain response to visual food cues in an extended satiety network using functional MRI scans acquired before and after a standardized meal.

Results: Higher-risk participants reported less subjective fullness (χ2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (χ2 = 3.92, P < 0.05), and consumed ∼350 more kilocalories than lower-risk participants (β = 348 kcal, P = 0.03), even after adjusting for fat or lean mass. Premeal, the higher-risk group had greater activation by "fattening" food images (compared with objects) in the medial orbital frontal cortex (β = 11.6; 95% CI: 1.5, 21.7; P < 0.05). Postmeal, the higher-risk subjects had greater activation by fattening (compared with nonfattening) food cues in the ventral tegmental area/substantia nigra (β = 12.8; 95% CI: 2.7, 23.0; P < 0.05), amygdala (β = 10.6; 95% CI: 0.7, 20.5; P < 0.05), and ventral striatum (β = 6.9; 95% CI: 0.2, 13.7; P < 0.05). Moreover, postmeal activation by fattening food cues within the preselected extended satiety network was positively associated with energy intake at the buffet meal (R2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R2 = 0.28, P = 0.01), amygdala (R2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R2 = 0.27, P = 0.01).

Conclusion: The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663.

Figures

FIGURE 1

Satiety, food appeal, and caloric intake in higher- compared with lower-risk FTO genotypes. All participants rated themselves as equally hungry across the study visit day (A). Individuals at higher risk for obesity (genotype AA) consistently rated themselves as less full across the visit day (P < 0.01, main effect of group) (B). Overall, appeal ratings for both “fattening” (C) and “nonfattening” (D) foods were lower postmeal [P < 0.001, P < 0.01, respectively; main effect of meal (a compared with b)]; however, individuals at higher risk for obesity rated fattening foods as more appealing overall [P < 0.05; main effect of group (c compared with d)]. Participants in the higher-risk group consumed more calories based on calculated daily caloric requirement at the ad libitum buffet (E). In panels A and B, arrows indicate consumption of a meal: up-arrow, breakfast (10% of estimated daily caloric need); down-arrow, standardized meal (20% of estimated daily caloric need); double-arrow, ad libitum buffet. Gray bars represent fMRI scans. Data are mean ± SEM, P values were determined by linear mixed models (A–D) and linear regression (E), and all models are adjusted for sex (lower risk, n = 91; higher risk, n = 20). **P < 0.05 compared with lower-risk group. FTO, fat mass and obesity-associated gene; VAS, visual analog scale.

FIGURE 2

Appetite-regulating hormones and glucose in higher- compared with lower-risk FTO genotypes. Participants at higher risk for obesity had similar fasting plasma leptin concentrations (A) and calculated HOMA-IR scores (B) compared with those at lower risk for obesity. The groups also had similar glucose (C) and insulin (D) profiles across the study visit day; however, after the standardized meal (t270), higher-risk participants had higher plasma insulin values. Plasma concentrations of ghrelin (E) and GLP-1 (F) did not differ between groups. In panels C–F, arrows indicate consumption of a meal [i.e., up-arrow, breakfast (10% of daily caloric need); down-arrow, standardized meal (20% of estimated daily caloric need)], and gray bars represent fMRI scans. Data are means ± SEMs, P values were determined by linear mixed models and are adjusted for sex (lower risk, n = 91; higher risk, n = 20). *P < 0.001 compared with lower-risk group. FTO, fat mass and obesity-associated gene; GLP-1, glucagon-like peptide 1.

FIGURE 3

Differences in brain activation between FTO genotype groups within regions of an extended satiety network. Gray panels depict the results for brain activation in response to fattening food cues (top: compared with objects; bottom: compared with nonfattening images). Premeal (left panel), the regions in which individuals at higher risk for obesity (based on FTO genotype) had significantly greater activation by fattening food cues than the lower risk group were the mOFC and ventral striatum, and a trend was present for the amygdala. Postmeal (right panel), the amygdala, ventral striatum, and VTA/SN also demonstrated significantly greater activation by fattening food cues in the higher-risk group. In contrast, participants at lower risk for obesity showed significantly greater activation by images of nonfattening foods (middle panel) in the ventral striatum (postmeal) and trends were present in the dorsal striatum (premeal) and the amygdala (postmeal). Data are β weights ± 95% CI, P values were determined by linear regression and are adjusted for sex (premeal: lower risk, n = 90; higher risk, n = 20; postmeal: lower risk, n = 88; higher risk, n = 20). *P < 0.05 compared with other group (Cohen's d = 0.44–0.62), #P < 0.085 compared with other group (Cohen's d = 0.39-0.46). FTO, fat mass and obesity-associated gene; mOFC, medial orbital frontal cortex; VTA/SN, ventral tegmental area/substantia nigra.

FIGURE 4

Anatomic locations of differences in activation between higher- and lower-risk FTO genotype groups. To provide anatomic specificity to the results presented in Figure 3, the locations of activation differences between FTO-based obesity risk groups were mapped using a descriptive voxelwise approach limited to the extended satiety network and VTA/SN. The left panel (premeal) shows clusters of greater activation in individuals at higher compared with lower risk (A, fattening > objects; B, fattening > nonfattening). The right panel (postmeal) shows clusters with greater activation in the higher-risk compared with the lower-risk groups (C, fattening > objects; E, fattening > nonfattening) and clusters with greater activation in lower-risk compared with higher-risk groups (D, nonfattening > objects). Z statistic maps were corrected for multiple comparisons and were thresholded at Z > 1.65 and a cluster significance threshold of P = 0.05 (FWE corrected across all ROIs examined; premeal: lower risk, n = 90; higher risk, n = 20; postmeal: lower risk, n = 88; higher risk, n = 20). Color scales provide Z values of functional activation. Montreal Neurological Institute coordinates are indicated. FTO, fat mass and obesity-associated gene; FWE, family-wise error; mOFC, medial orbital frontal cortex; ROI, region of interest; VTA/SN, ventral tegmental area/substantia nigra.

FIGURE 5

Greater ad libitum caloric intake is related to postmeal brain activation by fattening food cues within an extended satiety network. A correlational analysis performed among all participants showed that brain activation measured in the satiated state (after intake of a standardized meal) was positively associated with subsequent ad libitum caloric intake at a buffet meal. For each individual, parameter estimates were calculated as the mean activation by fattening food cues (compared with objects) across all regions within the extended satiety network (amygdala, insula, dorsal striatum, ventral striatum, and mOFC). Pearson's correlation coefficient and P value were derived from generalized estimating equation. Data are adjusted for sex (n = 108). mOFC, medial orbital frontal cortex.